Structure and Function of the Human Ryanodine Receptors and Their Association with Myopathies—Present State, Challenges, and Perspectives

• Main Authors: Vladena Bauerová-Hlinková, Dominika Hajdúchová, Jacob A. Bauer
• Format: Article
• Language: English
• Published: MDPI AG 2020-09-01
• Series: Molecules
• Subjects: ryanodine receptor; mutation; crystal structure; cryo-electron microscopy; molecular dynamics; normal mode analysis
• Online Access: https://www.mdpi.com/1420-3049/25/18/4040

Cardiac arrhythmias are serious, life-threatening diseases associated with the dysregulation of Ca<inline-formula><math display="inline"><semantics><msup><mrow></mrow><mrow><mn>2</mn><mo>+</mo></mrow></msup></semantics></math></inline-formula> influx into the cytoplasm of cardiomyocytes. This dysregulation often arises from dysfunction of ryanodine receptor 2 (RyR2), the principal Ca<inline-formula><math display="inline"><semantics><msup><mrow></mrow><mrow><mn>2</mn><mo>+</mo></mrow></msup></semantics></math></inline-formula> release channel. Dysfunction of RyR1, the skeletal muscle isoform, also results in less severe, but also potentially life-threatening syndromes. The <i>RYR2</i> and <i>RYR1</i> genes have been found to harbor three main mutation “hot spots”, where mutations change the channel structure, its interdomain interface properties, its interactions with its binding partners, or its dynamics. In all cases, the result is a defective release of Ca<inline-formula><math display="inline"><semantics><msup><mrow></mrow><mrow><mn>2</mn><mo>+</mo></mrow></msup></semantics></math></inline-formula> ions from the sarcoplasmic reticulum into the myocyte cytoplasm. Here, we provide an overview of the most frequent diseases resulting from mutations to RyR1 and RyR2, briefly review some of the recent experimental structural work on these two molecules, detail some of the computational work describing their dynamics, and summarize the known changes to the structure and function of these receptors with particular emphasis on their N-terminal, central, and channel domains.